This invention relates to novel sulfonamide compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS and other disorders.
WO 97/29097, WO 98/48681 and WO 97/49695 all disclose a series of sulfonamide derivatives that are 5-HT7 receptor antagonists and are useful in the treatment of various CNS diseases. Malleron et al (J. Med. Chem., 1993, 36, 1194-1202) discloses a series of indole derivatives that are claimed to act as potent and selective serotonin uptake inhibitors.
A structurally novel class of compounds has now been found which also possess 5-HT7 receptor antagonist activity. The present invention therefore provides, in a first aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof: 
wherein:
Q is phenyl or thienyl;
R1 is halogen, hydroxy, C1-6alkyl, CF3, OCF3 or C1-6alkoxy;
m is 0, 1, 2 or 3;
R2 is C1-4alkyl;
X is nitrogen, carbon or CH,
 is a single bond when X is nitrogen or CH or
 is a double bond when X is carbon;
D is a single bond, Cxe2x95x90O, O or CH2 subject to the proviso that when X is nitrogen then D is not oxygen;
P is phenyl, naphthyl, a 5 or 6 membered heteroaryl ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or a benzofused heteroaryl ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur;
R3 is C1-6alkyl optionally substituted by NR4R5, aryl, arylC1-6alkyl, C1-6alkoxy, C1-6alkylthio, cyano, hydroxy, nitro, halogen, CF3, C2F5, NR4R5, CONR4R5, NR4COR5, S(O)pNR4R5, CHO, OCF3, SCF3, CH2OR6, CO2R6 or COR6 where p is 0, 1 or 2 and R4, R5 and R6 are independently hydrogen, C1-6alkyl, aryl or arylC1-6akyl;
n is 0, 1, 2 or 3.
Alkyl groups whether alone or as part of another group may be straight chain or branched. The term xe2x80x98halogenxe2x80x99 is used herein to describe, unless otherwise stated, a group selected from fluorine, chlorine, bromine or iodine. The term xe2x80x98arylxe2x80x99 is used herein to describe, unless otherwise stated, a group such as phenyl or naphthyl optionally substituted by one or more C1-6alkyl or halogen. The term xe2x80x98naphthylxe2x80x99 is used herein to denote, unless otherwise stated, both naphthalen-1-yl and naphthalen-2-yl groups.
When Q is thienyl a preferred group is thien-2-yl. Preferably Q is phenyl.
When m is 1, R1 is preferably halogen (particularly fluorine or chlorine), a C1-6alkyl group (particularly methyl, ethyl, isopropyl or t-butyl), CF3 or C1-6alkoxy group (particularly methoxy or ethoxy). When m is 2 or 3 the groups R1 may be the same or different.
When Q=phenyl and m=1 preferred examples include moieties in which R1 is either a fluoro group with a para relationship with respect to the sulfonamide group or is a methyl group with a meta relationship with respect to the sulfonamide linkage. When Q=phenyl and m=2 preferred examples include those in which the R1 groups are independently halogen or C1-6alkyl substituted at the 2, 3 or 2, 4 positions with respect to the sulfonamide linkage. When Q=phenyl and m=3 preferred examples include those in which the R1 groups are independently halogen (particularly chloro), C1-6alkyl (particularly methyl) or CF3 substituted at the 2, 4 and 5 positions with respect to the sulfonamide linkage.
Suitable examples of R2 groups include methyl, ethyl, isopropyl or n-butyl. Preferably R2 is methyl or isopropyl, most preferably isopropyl.
Preferably X is nitrogen or CH such that  is a single bond. Most preferably X is CH.
Preferably D is a single bond.
When P is a 5 or 6 membered heteroaryl ring suitable examples include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrrolidinyl and pyrazinyl. When P is a benzofused heteroaryl ring suitable examples include indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl and isoquinolinyl. The heterocyclic groups listed above can be linked to the remainder of the molecule via a carbon atom or, when present, a suitable nitrogen atom. It will be appreciated however, that when D is O then the heteroaryl ring must be linked to the rest of the molecule via a carbon atom. Preferably P is phenyl, naphthyl, pyrirnidin-2-yl or is a benzofused heteroaryl ring selected from the group consisting of quinolin-4yl, 2-oxo-2,3-dihydrobenzimidazol-1-yl, 2-oxo-2,3-dihydrobenzaxazol-1-yl, indol-3-yl, indol-2-yl, benzoxazol-2-yl, benzothiazol-2-yl and particularly benzimidazol-2-yl.
When n is 1, R3 is preferably halogen (particularly fluorine or chlorine), a C1-6alkyl optionally substituted by NR4R5 (particularly methyl), hydroxy, CF3, C1-6alkoxy (particularly methoxy) or groups COR6 or CO2R6 in which R6 is methyl. When n is 2 or 3 the groups R3 may be the same or different. Preferably n is 0 or 1.
Particularly preferred compounds of the invention include:
N-(2-(4-(1H-Benzimidazol-2-yl)-piperidin-1-yl)-ethyl)-3,N-dimethyl benzene sulfonamide,
3,4 Dichloro-N-(2-(4(1H-indol-3-yl)-piperidin-1-yl)-ethyl)-N-methyl-benzene sulfonamide,
2,4,5-Trichloro-N-ethyl-(2-(4-(5-fluoro-1H-benzimidazol-2-yl)-piperidin-1-yl)-ethyl)-benzene sulfonamide,
2,4,5-Trichloro-N-(2-(4-(5-fluoro-1H-benzimidazol-2-yl)-piperidin-1-yl)-ethyl)-N-isopropyl benzene sulfonamide,
4-Chloro-2,5-dimethyl-N-(2-(4-(5-fluoro-1 H-benzimidazol-2-yl)-piperidin-1-yl)-ethyl)-N-isopropyl benzene sulfonamide,
N-(2-(4-(1H-Benzimidazol-2-yl)-piperazin-1-yl)-ethyl)-2,4,5-trichloro-N-isopropyl-benzene-sulfonamide,
3,N-Dimethyl-N-(2-(4-(2-methyl-1H-indol-3-yl)-3,6dihydro-2H-pyridin-1-yl)-ethyl)-benzene sulfonamide,
4-Fluoro-(N-(2-(4-(2-oxo-2,3-dihydro-benzimidazol-1-yl)3,6-dihydro-2H-pyridin-1-yl)ethyl)-benzene sulfonamide,
2,3,4-Trichloro-N-(2-(4-(5-fluoro-1H-benzimidazol-2-yl)-piperidin-1-yl)-ethyl-N-methyl-benzene-sulfonamide,
2,5-Dibromo-N-(2-(4-(5-fluoro-1H-benzimidazol-2-yl)-piperidin-1-yl)-ethyl-N-methyl-benzene-sulfonamide,
2,4-Dichloro-N-(2-(4-(5-fluoro-1H-benzimidazol-2-yl)-piperidin-1-yl)-ethyl-5,N-dimethyl-benzene-sulfonamide,
4,5-Dichloro-N-(2-(4-(5-fluoro-1H-benzimidazol-2-yl)piperidin-1-yl)-ethyl)-N-methyl-2-trifluoromethyl-benzenesulfonamide,
2-Chloro-4-fluoro-N-(2-(4-(5-fluoro-1H-benzimidazol-2-yl)-piperidin-1-yl)-ethyl-N-methyl-benzene-sulfonamide,
N-(2-(4-(1H-Benzimidazol-2-yl)-piperazin-1-yl)-ethyl)-3,N-dimethyl benzene sulfonamide,
N-2-(4-(1H-Benzimidazol-2-yl)-piperazin-1-yl)-ethyl)-2,4,5-trichloro-N-methyl-benzenesulfonamide,
2,4,5-Trichloro-N-(2-(4-(5-fluoro-1H-benzimidazol-2-yl)piperazin-1-yl)-ethyl)-N-methyl benzene sulfonamide,
4-Fluoro-N-(2-(4-(2-methoxyphenyl)-piperazin-1-yl)-ethyl)-N-methyl benzene sulfonamide
N-{2-[4-(1H-Benzimidazol-2-yl)-piperazin-1-yl]-ethyl}-2,4-dichloro-5,N-dimethyl-benzenesulfonamide
or a pharmaceutically acceptable salt thereof
Other preferred compounds of this invention include those shown in Tables 1-5 below.
The compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, futmaric, salicylic, citric, lactic, mandelic, tartaric and methanesulphonic.
Compounds of formula (I) may also form solvates such as hydrates, and the invention also extends to these forms. When referred to herein, it is understood that the term xe2x80x98compound of formula (I)xe2x80x99 also includes these forms.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms including diastereomers and enantiomers and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof.
The present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises coupling a compound of formula (II): 
in which Q, R1, R2 and m are as defined in formula (I) and Y is a leaving group with a compound of formula (III): 
in which , X, D, P, n and R3 are as defined in formula (I);
and optionally thereafter if appropriate:
removing any protecting groups;
forming a pharmaceutically acceptable salt.
Suitable leaving groups Y include halogen (particularly chloro) and xe2x80x94OSO2Ar groups such as tosylate. The reaction of a compounds of formulae (II) and (III) is preferably carried out in a solvent such as acetonitrile or dichloromethane optionally in the presence of sodium iodide and a base such as potassium carbonate.
Those skilled in the art will appreciate that it may be necessary to protect certain groups. Suitable protecting groups and methods for their attachment and removal are conventional in the art of organic chemistry, such as those described in Greene T. W. xe2x80x98Protective groups in organic synthesisxe2x80x99 New York, Wiley (1981).
Compounds of formulae (II) and (III) are either commercially available or are prepared using methods described herein or analogous to known methods.
Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.
Compounds of formula (I) and their pharmaceutically acceptable salts have 5-HT7 receptor antagonist activity and are believed to be of potential use for the treatment or prophylaxis of certain CNS disorders such as anxiety, depression, sleep disorders (including disturbances of Circadian rhythms), migraine, Parkinson""s disease, schizophrenia, pain, appetite disorders and other indications such as inflammation, spastic colon, renal disorders, hypotension, cardiovascular shock, stroke, septic shock and gastrointestinal diseases such as IBS (irritable bowel syndrome).
Thus the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt or a solvate thereof, for use as a therapeutic substance, in particular in the treatment or prophylaxis of the above disorders. In particular the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof or a solvate thereof for use in the treatment or prophylaxis of depression, migraine and/or sleep disorders.
In another aspect the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or a solvate thereof, for the manufacture of a medicament for the treatment or prophylaxis of the above disorders.
The invention further provides a method of treatment or prophylaxis of the above disorders, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a solvate thereof.
The present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusable solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colourants.
For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; and such unit doses may be administered more than once a day, for example two or three a day, so that the total daily dosage is in the range of about 0.5 to 100 mg; and such therapy may extend for a number of weeks or months.
When administered in accordance with the invention, no unacceptable toxicological effects are expected with the compounds of the invention.